Linking traumatic brain injury and accelerated bone regeneration - a central role of alpha-adrenergic/CGRP signaling.

骨折愈合受损是一个持续的临床挑战，因为治疗选择仍然有限。因此，从机制上理解创伤性脑损伤（TBI）对骨折修复的积极影响具有巨大的治疗潜力。使用实验方法，我们以前证明，骨痂形成增加，结合手术诱导的创伤性脑损伤和股骨骨折的小鼠模型。在我们目前的工作中，我们能够更详细地阐明TBI和骨再生之间复杂的病理生理过程。作为一个潜在的关键因素，我们能够确定增加的α-肾上腺素能/CGRP信号传导，介导TBI后加速骨再生。具体来说，我们提出，TBI的结果在交感神经张力的暂时上升，导致去甲肾上腺素（NE）的释放从神经末梢在骨微环境。在完整骨中，这导致通过β-肾上腺素能信号传导抑制骨形成。然而，在骨折骨中，TBI后NE的暂时升高通过激活α-肾上腺素能受体、刺激局部CGRP合成和成骨细胞前体的激活促进骨再生。我们目前的研究结果提出了需要解决的具体问题，以充分了解连接骨和脑损伤的调节回路。拟议的研究TBI和骨再生之间的串扰，以及α-肾上腺素能/CGRP信号传导的理解，作为其假定的中心元素，可能有助于开发新的治疗策略，患者患有受损的骨折修复。

Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Therefore, the mechanistic understanding why traumatic brain injury (TBI) positively affects fracture repair holds great therapeutic potential. Using an experimental approach, we previously demonstrated that callus formation is increased in a mouse model combining surgically induced TBI and fracture of the femur. In our current work, we were able to elucidate the complex pathophysiologic processes linking TBI and bone regeneration in more detail. As a potential key element, we were able to identify increased alpha-adrenergic/CGRP signaling, which mediates accelerated bone regeneration following TBI. Specifically, we propose that TBI results in a temporary rise in sympathetic tone, resulting in norepinephrine (NE) release from nerve endings in the bone microenvironment. In intact bone, this leads to the inhibition of bone formation through beta-adrenergic signaling. In fractured bone however, the temporary rise of NE following TBI promotes bone regeneration through the activation of alpha-adrenergic receptors, the stimulation of local CGRP synthesis, and the activation of osteoblast precursors. Our current results raise specific questions that need to be address in order to fully understand the regulatory circuits linking bone and brain injury. The proposed study on the crosstalk between TBI and bone regeneration, as well as the comprehension of alpha-adrenergic/CGRP signaling as its putative central element, may aid in developing new therapeutic strategies for patients suffering from impaired fracture repair.